Approximately one in ten couples is infertile. In almost one quarter of cases of infertility, the cause cannot be determined. Studies in humans and other mammals suggest that a significant fraction of cases of infertility have a genetic basis, although many of the responsible genes have yet to be identified. One potential cause of infertility involves genetic defects in cellular metabolism. The goal of this project is to assess how inherited metabolic disorders affect fertility using the mouse as a model system. Specifically, this project will study the development of the female germline and early embryos in mice with mutations that impair two central metabolic pathways, glycolysis and the tricarboxylic acid (TCA) cycle. In vitro studies have suggested that oocytes and embryos utilize these pathways, although this observation has not been confirmed in vivo. Using a genetic approach, the proposed studies will be able to establish the role of these metabolic pathways in vivo. Additionally, these studies will provide some of the first insight into the ability of oocytes and embryos to adapt to impairments in their normal metabolic processes. The specific aims of this project are: (1) to assess the effect of a mutation that impairs utilization of the TCA cycle on development of the female germline and (2) to assess the effects of mutations that impair glycolysis and the TCA cycle on early embryogenesis. The proposed studies will combine a number of approaches to assess the development and metabolism of oocytes and embryos that carry these mutations. In addition to identifying potential causes of infertility, these studies may improve techniques of assisted reproduction. Studies of embryos with metabolic abnormalities may lead to the development of improved culture conditions or new methods for selecting embryos with the best developmental potential. [unreadable] [unreadable]